Renal cancer is a devastating malignancy that is highly resistant to medical therapy. The VHL tumor suppressor is mutated in most adult renal cancers. Yet, the mechanism of VHL tumor suppression is not known. Using a directed approach to find VHL-interacting proteins important in renal cancer, our laboratory has identified Jade-1 (gene for Apoptosis and Differentiation in Epithelia) as a particularly strong VHL interactor. Jade-l, a novel, kidney-enriched, PEST and plant homeodomain protein, is a member of a new protein family. Jade-1 is a short-lived target of the proteasome degradation pathway and is strongly pro-apoptotic, as it decreases cellular adhesion and directly promotes chromatin compaction. VHL blocks Jade-l-induced apoptosis and stabilizes Jade-1 protein, which is a new VHL function. Moreover, we have now shown that Jade-1 stabilization is VHL mutation-dependent, with non-renal cancer-causing VHL missense mutations able to stabilize Jade-1 like wild-type VHL. Jade-1 stabilization is therefore the first VHL activity to show substantial correlation with renal cancer risk, suggesting it has a disease relationship. Stabilization of Jade-1 by VHL is highly specific, as it has not been observed with known or potential VHL partners. Jade-1 is hypoxia-inducible in a VHL dependent manner and shows evidence of altered post-translational modification in conditional VHL null mice. Thus, we have established convincing evidence of the VHL-Jade-1 relationship's authenticity as well as Jade-1 's compelling biological significance. We propose the following Aims: 1. The VHL-Jade-1 protein-protein interaction, and Jade-1 expression in renal cancer tissue 2. VHL-dependent Jade-1 stabilization and modification 3. Jade-1 in apoptosis and cell stress, and modulation by VHL 4. Jade-1 as a transcription factor and in chromatin compaction, and modulation by VHL